The present invention is directed to radioactive compounds useful for therapy.
Radionuclide therapy is the use of internally administered, unsealed pharmaceuticals whereby: sufficient radioactivity, in suitable composition, is administered to a patient: distribution of radioactivity occurs in vivo according to the route of administration and the biochemical properties of the radioactive drug; and internal irradiation occurs according to the pharmacologic fate and the physical decay properties of the radionuclide.
A limitation to radionuclide therapy is the requirement for selective toxicity: the benefit of injuring diseased tissue must exceed the risk of injuring healthy tissues. Many radioactive compounds are known, yet few yield selective toxicity sufficient to prove useful for radionuclide therapy. Therefore, a general need remains to discover additional or improved compounds so as to maximize irradiation of diseased tissue and to minimize irradiation of healthy tissue.
One basis for selective toxicity is in vivo localization: the chemical nature of the radioactive drug is preferred such that the radioactivity concentrates in diseased tissue. A variety of radio labeled compounds have been made that concentrate in diseased tissue, yet most disease-avid radioactive compounds concentrate insufficiently to prove suitable for radionuclide therapy. An example is .sup.131 I-albumin. Therefore, a specific need remains to discover additional or improved radioactive compounds that concentrate to a high degree in diseased tissue.
Another basis for selective toxicity is conferred by products of physical decay: emissions are preferred that deposit energy effectively in tissue. A variety of highly disease-avid radiopharmaceuticals are known, yet most emit decay products whose energy deposited in tissue is unsuitably concentrated for radionuclide therapy. Examples are radiopharmaceuticals labeled with .sup.99m Tc, .sup.67 Ga, .sup.111 In, and .sup.123 I. Among types of emissions, irradiation is: poorly concentrated by uncharged, massless particles such as photons: better concentrated by charged, low mass particles, such as electrons; and best concentrated by charged, massive particles, such as alpha-particles. Therefore, a specific need remains to discover additional or improved radioactive compounds that abundantly emit electrons or alpha-particles.
Alpha-particle emitting pharmaceuticals have not been used for therapy of human diseases, except for rare examples of intracavitary use. Systemic use of alpha-emitting pharmaceuticals has been altogether unsuitable. Therefore, a general need remains to discover additional alpha-particle emitting pharmaceuticals suitable for therapeutic use in humans.
A limitation to using alpha-particle emitting pharmaceuticals for radionuclide therapy is the requirement for a short physical half-life and stable daughter radionuclide(s). As such, a large number of alpha-particle emitting radionuclides are known, but only two are suitable for use in radionuclide therapy: .sup.212 Bi and .sup.211 At. Of these, the 7 hour-life of .sup.211 At is more suitable for most radiopharmaceutical carriers. Therefore, a specific need remains to discover additional .sup.211 At-labeled pharmaceuticals suitable for human diseases.
A general limitation to medical therapy encompasses numerous diseases for which present therapy is limited or unsuitable. Various treatments, including combination of surgery, chemotherapy, immunotherapy or radiation therapy, are unsuitable for treatment of neuroendocrine tumors, a class of tumors sharing histological and biochemical features. For example, neuroblastoma, possibly the most common solid malignancy of childhood, is usually advanced at the time of diagnosis, such that 80-90% of children with the disease die within 1-2 years despite the best therapy available. Therefore, a general need remains to discover additional or improved therapies for neuroendocrine tumors, including neuroblastoma.
It is therefore the object of the present invention to provide alpha-emitting pharmaceuticals, which, are reliably safe and effective for therapy of neuroendocrine tumors, including neuroblastoma.
This and other objects will become apparent from the following description and claims.